Project Summary Chiral ?,?-Disubstituted Amine Synthesis by Dynamic Kinetic Resolution Overview: This program targets a new paradigm in the synthesis of chiral ?,?-disubstituted amines. This will be accomplished by enabling a dynamic kinetic resolution of allylic azides. This approach takes advantage of the innate properties of allylic azides and the allylic azide rearrangement. The proposed pathway is significant and unique because it would establish the chirality of these amines without directly forming a C-C or C-N bond. Instead, this approach brings additional functionality to the product while simultaneously establishing the chiral ?,?-disubstituted center. The various phases of this proposal concern expanding upon preliminary results to a wide array of target systems. Three different approaches are provided to differentiate non-symmetric allylic systems and include using: i) conjugation, ii) proximity effects, and iii) sterics. Each of these approaches is capable of providing synthetically useful amines or amine surrogates. Many of the most common heterocycles, including those present in a series of BACE-1 inhibitors, are conceivably available by one of these approaches. Relevance to Public Health: Most pharmaceutical agents contain an amine or amine derivative. In many cases, the carbon to which the amine is bound is a stereocenter. The configuration of this center is essential to controlling the intended pharmacological effect. For simple amines, many efficient methods can establish the desired chirality. However, for highly substituted amines, this is not the case. Robust and general methods are lacking. BACE-1 inhibitors are an illustrative family. In the last several years, dozens of BACE-1 inhibitors have been disclosed from >10 major pharmaceutical companies. All contain this motif. In all cases, establishing this stereocenter was problematic. Supporting this program would simplify the syntheses of these chiral amines and make them available for applications in medicinal chemistry and chemical biology.